The Future: A Pill To Prevent Cognitive Decline?
Why not exercise?

For many years scientists believed that the adult human brain was not able to make new cross connections. Neurons were thought to stop functioning and die at a high rate as one aged. Altman, in 1964, hypothesized that vertebrates could create new neurons, but this did not become a prevailing view until much later. Neural plasticity, the ability of

Andrew Pieper, M.D., Ph.D.

the brain to change and respond to conditions and experiences was believed to get worse and worse each year. This is not the case. A number of studies have shown that the brain continues to be active, nerves can “learn” and cross connect actively, and aging doesn’t inevitably lead to a severe cognitive decline. Dementia also, is not inevitable. And exercise makes it significantly less likely.

Science Friday recently interviewed researcher Steven McKnight and reported on a new study that came up with what may be the first pill to lessen cognitive decline. The study was performed on rats and looked at the impact of P7C3 on the dentate gyrus of the hippocampus. The authors conclusions were:

• P7C3 stabilizes mitochondrial membrane potential and inhibits newborn neuron apoptosis (programmed cell death)
• P7C3 corrects hippocampal deficits in mice devoid of adult neurogenesis
• P7C3 preserves cognitive capacity in aged rats

But, just as studies have shown that for many cases exercise can help with depression and sometimes be better than the “pills”, exercise has already been shown to be a good inhibitor in humans of both cognitive decline and dementia. The authors of the P7C3 study even noted that rats who perform voluntary exercise have a lower cognitive decline associated with aging. And social integration of the rats is another “environmental” factor associated with a decreased risk of cognitive decline.

While you are waiting for clinical trials and FDA approval of P7C3 and the “lose weight magic pill” you can take action today. Besides, the active ingredient of the pill already has a patent pending. So, get out there and exercise. Exercise should be a life long activity. If you find as you age that you can no longer do the same exercise you were doing before, it isn’t hard to find other activities to substitute. Run, walk, swim, bike, elliptical, rowing machine are all fine ways to get aerobic exercise. Body weight exercise, dumbbells, or machines all work well for strength training. The exercise recommendation is:

30 minutes of moderate aerobic exercise – 5 days per week
(or 20 minutes vigorous aerobic exercise – 3 days per week)
2 days of strength training each week

Related:

What Made The Brain Get Bigger: Exercise and Evolution

References:

Altman J. Are new neurons formed in the brains of adult mammals? Science. 1962 Mar 30;135:1127-8.

He XZ, Baker DW. Body mass index, physical activity, and the risk of decline in overall health and physical functioning in late middle age. Am J Public Health. 2

Laurin D, Verreault R, Lindsay J, MacPherson K, Rockwood K. Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch Neurol. 2001;58(3):498-504

McKnight, S.L., Pieper, A.A., Ready, J.M., DeBrabander, J. July 2010. Proneurogenic compounds. U.S. patent 2010/020681.

Piepersend A, Xie S, Capota E, et. al. Discovery of a Proneurogenic, Neuroprotective Chemical. ell, Volume 142, Issue 1, 39-51, 9 July 2010 10.1016/j.cell.2010.06.018

Strawbridge WJ, Deleger S, Roberts RE, Kaplan GA. Physical activity reduces the risk of subsequent depression for older adults. Am J Epidemiol. 2002;156(4):328-334.

Smith et. al. Aerobic Exercise and Neurocognitive Performance: A Meta-Analytic Review of Randomized Controlled Trials. Psychosom. Med. 2010;72:239-252.

van Praag, H., Kempermann, G., and Gage, F.H. (1999). Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 2, 266–270.

Yaffe K, Barnes D, Nevitt M, Lui LY, Covinsky K. A prospective study of physical activity and cognitive decline in elderly women: women who walk. Arch Intern Med. 2001;161(14):1703-1708.

Many people have played the facebook game “What’s Your Real Age”. My guess that those who played it wanted to feel they were younger than their biological age. Telomere length seems to be the real way to determine actual “biological age”. These are the real “biological clocks”. Telomeres are repetitive sequences at the ends of chromosomes that shorten with age and also shorten in certain metabolic and disease states. They are sometimes called the protective “caps” on the ends of chromosomes. Because of the manner in which chromosomes are replicated during cellular division, a bit of the telomere is not copied with each subsequent cellular generation resulting in a gradual shortening of the telomere restriction fragment (TRF) length.

Telomeres Shorten With Age

A recent study showed that people who perform more leisure time physical activity have longer telomeres. Another recent study, with an admitted low subject number, demonstrated that eating processed meat  such as sliced bologna would also slice down the size of your telomeres. This study, published in the American Journal of Clinical Nutrition did not find other expected dietary associations.

The Cardiovascular Health Study (2007) found inverse correlations (shortened telomeres) between TRF length and fasting glucose level, fasting insulin level, systolic and diastolic blood pressure, carotid intima-media thickness, interleukin-6, high BMI, overweight (in men).

Some studies including one with “voluntary running” in mice showed the production of telomere protective compounds with the “voluntary” running. On a side note,  I’ll have to look closer at this study. If we can can get mice to  voluntarily participate in a “fitness” program, maybe we can figure out the secret to get more people to do so. Perhaps cheese is the answer.

Aubert and Lansdorp (2008) published an excellent review of  the biology of telomeres and aging. They noted that Barbara McClintock, in her 1983 Nobel acceptance speech pointed out the significance of cellular response to stress and dangers. “In the future attention undoubtedly will be centered on the genome, and with greater appreciation of its significance as a highly sensitive organ of the cell, monitoring genomic activities and correcting common errors, sensing the unusual and unexpected events, and responding to them, often by restructuring the genome. We know about the components of genomes that could be made available for such restructuring. We know nothing, however, about how the cell senses danger and instigates responses to it that often are truly remarkable.”

Short Telomeres Trigger Cellular Defences

The shortened telomeres are likely sending more “damage” signals to the cells which lead to a number of biochemical pathways which degrade the contents of the cell. Studies on cellular senescence, apoptosis, and research on genomics is leading us to a better understanding, but we have a long ways to go. The complexity never ends, but it continues to unwind. And you can almost hear the tick tock of the biological clock. Your best means of slowing up the ticking are life habit changes: exercise regularly, maintain healthy body weight, don’t smoke and eat a healthy diet.
What’s my age again? – Blink 182

What's My Age Again?

References:

Lynn F. Cherkas, PhD; Janice L. Hunkin, BSc; Bernet S. Kato, PhD; J. Brent Richards, MD; Jeffrey P. Gardner, PhD; Gabriela L. Surdulescu, MSc; Masayuki Kimura, MD, PhD; Xiaobin Lu, MD; Tim D. Spector, MD, FRCP; Abraham Aviv, MD. Arch Intern Med. 2008;168(2):154-158.

Annette L. Fitzpatrick1, Richard A. Kronmal2, Jeffrey P. Gardner3, Bruce M. Psaty1,4, Nancy S. Jenny5, Russell P. Tracy5,6, Jeremy Walston7, Masyuki Kimura3 and Abraham Aviv . Leukocyte Telomere Length and Cardiovascular Disease in the Cardiovascular Health Study. American Journal of Epidemiology 2007 165(1):14-21; doi:10.1093/aje/kwj346.

J. A Nettleton, A. Diez-Roux, N. S Jenny, A. L Fitzpatrick, and D. R Jacobs Jr. Dietary patterns, food groups, and telomere length in the Multi-Ethnic Study of Atherosclerosis (MESA). Am. J. Clinical Nutrition, November 1, 2008; 88(5): 1405 – 1412

Liza S.M. Wong, Hisko Oeseburg, Rudolf A. de Boer, Wiek H. van Gilst, Dirk J. van Veldhuisen and Pim van der Harst.. Telomere biology in cardiovascular disease: the TERC–/– mouse as a model for heart failure and ageing. Cardiovascular Research 2009 81(2):244-252; doi:10.1093/cvr/cvn337

Aubert, G. and P. M. Lansdorp (2008). “Telomeres and Aging.” Physiol. Rev. 88(2): 557-579.

For many people, long trips disturb the natural rhythms so much that normal functioning on both the physical and intellectual planes is impaired. Clearly, there is a need for some method to improve the travel experience and the race results for those on a tight schedule. First class? Sounds great, but isn’t practical and probably won’t get the job done.

Circadian rhythms may affect racing performance. Most world records have been set in the afternoon or evening rather than in the morning. It may be a matter of when the races are run, but it also may follow along with optimal body rhythms. Workouts seem easier in the afternoon, joints are stiffer in the morning, and some old lecture notes I have indicate that muscles are weakest at 8 AM & 8 PM and strongest at 5 PM. Body temperature reaches a peak around 5PM. (Spiking fevers when you are ill, do not spike in the morning, but late afternoon or evening.) Measured VO2 MAX is greater in the afternoon.

Adapting:

Suggestions

• Start sleeping on the schedule of where you will be racing (or working).
• If you can, train on the schedule of where you will be headed.
• Get there early if you can, for optimal performance one day for every hour time difference. Otherwise follow all the other suggestions.
• Melatonin
• Bright lights for wake up time on new schedule and wake up also.
• Eat lightly 2 days before travel, then start eating on the arrival schedule

The suggested eating change, of eating on the new arrival schedule comes as a result of a new study on circadian rhythms published in this weeks Science Magazine. The article notes that when food is readily available, circadian rhythms are greatly impacted by the light-dark cycle. If food is only available at night, the animal will shift its circadian rhythms to match the time when food is available. This led to studies of the gene clock Bmal1 and found that the dorsomedial hypothalamic nucleus seemed to impact the role of food and feeding on the circadian timing system (CTS). Light has previously been found to play a role via retinal ganglion cells containing melanopsin which generates signals to the suprachiasmatic nuclei (SCN) of the hypothalamus. The SCN then effects a tuning of the circadian rhythms via synaptic and humoral mechanisms. The studies described here were done on mice.

The authors conclusions were:

Our data indicate that there is an inducible clock in the DMH that can override the SCN and drive circadian rhythms when the animal is faced with limited food availability. Thus, under restricted feeding conditions, the DMH clock can assume an executive role in the temporal regulation of behavioral state. For a small mammal, finding food on a daily basis is a critical mission. Even a few days of starvation, a common threat in natural environments, may result in death. Hence, it is adaptive for animals to have a secondary “master clock” that can allow the animal to switch its behavioral patterns rapidly after a period of starvation to maximize the opportunity of finding food sources at the same time on following days.

The biological clock for mammals, clearly resides in the hypothalamus. In some insects and snails, the clocks seem to be located in the retina. In birds, the pineal gland has been thought to come into play, along with the hypothalamus. Photoreceptors are usually linked into the timing system, to synchronize the clock with the 24 hour day. Old studies showed light to be able to assist in resetting the clock by impacting genes, sleep patterns, alertness, and body temperature.

As we noted above, exercising on the new schedule, can also help. Recent research agrees with this as per the study “Scheduled exposures to a novel environment with a running-wheel differentially accelerate re-entrainment of mice peripheral clocks to new light–dark cycles (Yujiro Yamanaka, Sato Honma and Ken-ichi Honma Genes to Cells (2008) 13, 497-507)

A study from 2001 demonstrated the liver enzyme production could be shifted 10 hours within 2 days by altering feeding. (Science 19 January 2001: Vol. 291. no. 5503, pp. 490 – 493 Entrainment of the Circadian Clock in the Liver by Feeding. Karl-Arne Stokkan, Shin Yamazaki, Hajime Tei, Yoshiyuki Sakaki, Michael Menaker)

Larks and Owls
While we don’t have studies to cite here, others have noted that some people are better at staying up late than others, while others are happy to wake up at 5 or 6am, but can’t stay up to party, play MMORPGs, or text their buddies in the middle of the night.

Some feel that it is easier for Larks to travel west to east and for owls to travel from east to west. The larks have little trouble staying up late, and have probably already shifted in part to the western time zone.